Stereospecific total steroidal synthesis via substituted c/d-trans indanones

ABSTRACT

Progestationally active steroids may be prepared by first reacting 4-active group substituted C/D trans indanones with substituted Beta -keto esters followed by cyclization to B,C,Dtricyclics having an A ring precursor group and then finally forming the desired steroid. Preferred Beta -keto esters for this purpose have the formula WHERE R7 is lower alkyl; R15 is oxo, lower alkylene-dioxy, arylenedioxy or (hydrogen and lower alkoxy); B is lower alkoxycarbonyl-methylene, aryloxy-carbonyl-methylene, cyano-methylene, lower alkyl sulfinyl-methylene, and lower alkyl sulfonylmethylene; and R25 and R26 are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl.

United States Patent Hajos 51 Sept. 19, 1972 [54] STEREOSPECIFIC TOTAL STEROIDAL SYNTHESIS VIA SUBSTITUTED C/ TRANS INDANONES [72] Inventor: Zoltan George Haios, Upper Montclair, NJ.

[73] Assignee: Hoffmann-La Roche Inc., Nutley,

[22] Filed: July 28, 1969 [21] Appl. No.: 845,546

Related US. Application Data [63] Continuation-impart of Ser. No. 765,023, Oct.

[52] US. Cl. ...260/340.5, 260/239.55 C, 260/240 R, 260/247.7 H, 260/268 C, 260/294.7,

[51] Int. Cl. ..C07d 13/10 [58] Field of Search ..260/340.5, 340.7, 340.9

[56] References Cited UNITED STATES PATENTS 7/1967 Pryde et a1 ..260/340.9

OTHER PUBLICATIONS Dorman, et al., Chemical Abstracts, (1968) Col. 29523n Vol. 68

Taguchi, et al., Chemical Abstracts, (1969) Col. 28739s Vol. 70

Primary ExaminerAlex Mazel Assistant Examiner-James H. Tumipseed Attorney-Samuel L. Welt, Jon S. Saxe, Bernard S. Leon, William H. Epstein and George M. Gould [57] ABSTRACT Progestationally active steroids may be prepared by first reacting 4-active group substituted C/D trans indanones with substituted fi-keto esters followed by cyclization to B,C,D-tricyclics having an A ring precursor group and then finally forming the desired steroid. Preferred B-keto esters for this purpose have the formula 5 Claims, No Drawings STEREOSPECIFIC TOTAL STEROIDAL SYNTHESIS VIA SUBSTITUTED C/D-TRANS INDANONES RELATED APPLICATIONS This application is a continuation-in-part of US. Pat. application, Ser. No. 765,023, filed Oct. 4, 1968.

BACKGROUND OF THE INVENTION SUMMARY OF THE INVENTION Pharmaceutically valuable steroids can be synthesized depending on the particular starting reactants selected by employing as intermediates bicyclic compounds of the formula 1 i: R, (IV) wherein m is an integer having a value of l or 2; R is hydrogen or lower alkyl; 2 is lower alkylene-dioxy methylene, CH(OR and "carbonyl; R when taken alone is hydrogen R when taken alone is lower alkoxycarbonyl, aryloxy-carbonyl, lower cycloalkyloxy-carbonyl, carbonyl-halide, hydrogen, carboxy, formyl and methylene-X, where X is a leaving group and when taken together are methylene; with the proviso that when Z is carbonyl R when taken alone is hydrogen; R when taken alone is carbonyl halide, hydrogen, carboxy, formyl and methylene-X where X is a leaving group and when taken together are methylene and R is hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl, lower alkanoyl, benzoyl, nitrobenzoyl, carboxy-lower alkanoyl, carboxy-benzoyl, trifluoroacetyl and camphorsulfonyl and reacting them in the case where R and R taken together are methylene or R is hydrogen and R is methylene-X with B-keto esters and other analogs of the formula O Ro-iil-B wherein R is selected from the group consisting of R R20 s and lower alkyl; R, is lower alkyl; R is selected from the group consisting of oxo, lower alkylenedioxy, arylenedioxy or (hydrogen and lower alkoxy); B is selected from the group consisting of lower alkoxy-carbonyl-methylene, lower aryloxy-carbonyl-methylene, cyanomethylene, lower alkyl sulfinyl-methylene, and lower alkyl sulfonyl-methylene, R and R are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl, R is lower alkyl or hydrogen, and R is lower alkyl, lower alkaryl, aralkyl or hydrogen.

In one aspect, this invention relates to a process for preparing intermediates useful in the preparation of tricyclic compounds of the formulas wherein R, is selected from the group consisting of hydrogen and lower alkyl where R R R R R and R" are as above; R is hydrogen or loweralkyl; R is hydrogen or COOR where R is hydrogen, lower alkyl or an alkali metal cation; Z is defined hereinafter and m is an integer having the value of l or 2.

Compounds of formula l-a may be converted into compounds of formula I-b by catalytic hydrogenation using a noble metal catalyst, e.g., palladium which, if desired, may be supported on a conventional catalyst support material, e.g., charcoal at normal conditions of temperature and pressure. A lower alkanol such as ethanol may be employed as solvent for this conversion.

Another aspect of this invention relates to a process for preparing intermediates which enable the direct preparation of steroids of the formulas II and III,

(III) and wherein R and m are as defined above; Z is defined hereinafter; R" is hydrogen or loweralkyl; R is hydrogen, aryl, alkaryl, aralkyl or lower alkyl and R and R are independently selected from the group consisting of lower alkyl, hydrogen and hydroxyl.

In accordance with this invention, it has been discovered that compounds of the formulas l-a, I-b, II and III above, can be synthesized depending on the particular starting reactants selected by employing as intermediates bicyclic compounds of the formula wherein m is an integer having a value of l or 2; R is hydrogen or lower alkyl; Z is lower alkylenedioxy methylene, CI-I(R and carbonyl; R when taken alone is hydrogen; R when taken alone is lower alkoxycarbonyl, aryloxy-carbonyl, lower cycloalkyloxy-carbonyl, carbonyl-halide, hydrogen, carboxy, formyl and methylene-X, where X is a leaving group and when taken together are methylene; with the proviso that when Z is carbonyl, R when taken alone is hydrogen; R when taken alone is carbonyl halide, hydrogen, carboxy, formyl and methylene-X where X is a leaving group and when taken together are methylene and R is hydrogen, lower alkyl, lower alkoxy-Iower alkyl, phenyl-lower alkyl, tetrahydropyranyl, lower alkanoyl, benzoyl, nitrobenzoyl, carboxy'lower alkanoyl, carboxy-benzoyl, trifluoroacetyl and camphorsulfonyl and reacting them in the case where R and R taken together are methylene or R is hydrogen and R is methylene-X with B-keto estersand other analogs of the formula where R is selected from the group consisting of lower alkyl; R, is lower alkyl; R is selected from the group consisting of 0x0, lower alkylenedioxy, arylenedioxy or (hydrogen and lower alkoxy); B is selected from the group consisting of lower alkoxy-carbonylmethylene, lower-aryloxy-carbonyl-methylene, cyanomethylene, lower alkyl sulfinyl-methylene, lower alkyl sulfonyl-methylene, and R and R are independently selected from the group consisting of hydrogen, hydroxyl and lower alkyl, R is lower alkyl or hydrogen and R" is lower alkyl, lower alkoxy, aralkyl and hydrogen.

In still another aspect, this invention relates to the preparation of the compounds of formula III above wherein R is hydrogen, by reacting the compounds of formulas IV-a and IV-c with a vinylogous cyclic-betaketo compound of the formula:

wherein R 2, m and X are as defined aforesaid; Y is selected from the group consisting of fluorine, chlorine, bromine and iodine and R':, is selected from the group consisting of lower alkyl, lower cycloalkyl and aryl.

DETAILED DESCRIPTION OF THE INVENTION In one aspect, this invention is concerned with novel indanones of the formulas IV, IV-a, IV-b, IV-c, IV-d,

lV-e and lV-f which are useful as chemical intermediates as described herein. Also, certain of the keto compounds of formula V are novel and are also considered within the scope of this invention. For purposes of convenience, the rings in formulas I and IV have been numbered. Throughout this specification, in the formulas of compounds containing asymmetric centers or in the designation of such compounds by chemical nomenclature, the desired enantiomeric form is shown or designated. However, unless explicitly indicated otherwise, such illustration and designation should be taken as comprehending the enantiomer shown or designated, as well as its optical antipode or their corresponding racemate. in the formulas presented herein, the various substituents on cyclic compounds are joined to the cyclic nucleus by one of two notations, a

solid line indicating a substituent which is in the B- orientation (i.e., above the plane of the paper), or a dotted line indicating a substituent which is in the Ol-Ol'llltfltiOll (below the plane of the paper).

As used herein, the term lower alkyl comprehends both and branched chain hydrocarbon moieties such as methyl, ethyl, isopropyl, n-propyl, t-butyl and the like, having 1 to 7 carbon atoms in the chain. The preferred compounds are those derivatives wherein R is methyl, ethyl and propyl which can be converted into steroids which exhibit exceptionally active pharmacological properties as hereinafter described. The formative lower alkyl" when used in expressions such as lower alkoxy-lower alkyl have the same significance. Thus, exemplary of the expression lower alkoxy-lower alkyl is a-ethoxy-ethyl and 3-propoxy-propyl. Exemplary of lower alkanoyl are acetyl and propionyl or other residues derived from lower alkane carboxylic acids of one to six carbon atoms; lower alkylenedioxy is understood to mean alkylene of one to six carbon atoms exemplary of which are l,2-ethylenedioxy, 2,2- dimethyl-l ,3-propylenedioxy, l ,2-propylenedioxy, 2,3- butylenedioxy, among other. Examples of arylenedioxyinclude phenylenedioxy, 1,2- naphthylenedioxy, 2,3-naphthylenedioxy, etc. The term nitrobenzoyl as used herein comprehends benzene moieties containing one or more nitro substituents, for example, nitrobenzoyl moieties such as 4- nitrobenzoyl and di-nitrobenzoyl moieties such as 3,5- dinitrobenzoyl. The expression carboxy-lower alkanoyl comprehends di-basic aliphatic acids of one to seven carbon atoms absent one OH moiety. Similarly, the expression carboxy-benzoyl denotes, for example, phthalic acids absent one OH moiety. The expression halide or halogen comprehends chlorine, fluorine, bromine and iodine. The expression lower alkoxy as utilized herein designates a lower alkyl ether group such as methoxy, ethoxy and the like, wherein the alkyl group is as defined above. The term lower alkoxy carbonyl methylene includes for example, ethoxy carbonyl-methylene. The term lower aryloxy carbonyl methylene" includes for example, phenyloxy carbonyl methylene. The term aryl comprehends phenyl or phenyl having one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, nitro, amine and halogen. The expression lower alkylaryl comprehends, for example, tolyl and ethylphenyl. The term cycloalkyl includes rings containing from one to six atoms, for example, cycloalkyl and cyclopentyl.

Especially preferred compounds of formula IV are those wherein 2" is lower alkoxy, especially t-butoxy although the other derivatives defined hereinabove can be suitably employed in accordance with the process of this invention.

The following schematic flow sheet entitled Reaction Scheme A, exemplifies the process routes em- REACIION SCHEME A VII) (VIII) R4 Z R4 Z 2) in m 1'1 0 0 Its (VIII-a) (IV-f) l A) l (5) R4 R4 R4 Z Z Z\ Y (hiring H1)... FY (0112)... 1 l l 1 y y: o

wherein R Z, m, R X and Y are as defined aforesaid.

ployed in accordance with the teachings of this invention for preparation via process routes (1), (2), (3), and the y inter" mediates of the formulas IV-c and IV-a, each of which can independently be reacted with the ,B-keto esters and other analogs thereof'of formula V to yield the end-products of formulas l-a, I-b, II and III as hereinafter detailed.

Thus, in one aspect of the process of this invention, comprises preparing compounds of the formula IV-a by the general reaction steps (I), (2) and (4) of Reaction Scheme A to which the numerals and letters in parenthesis are referenced in the following descrip' tions.

Many of the indanone starting reactants of formula VII wherein Z is carbonyl are known. They may be conveniently synthesized by methods known in the art, for example, by the Michael addition of methyl-vinylketone to 2-lower alkyl-cylco-pentane-l,3-dione. The cyclization can be effected using pyrrolidine in a benzene solvent under reflux reaction conditions (of, U.S. Pat. No. 3,321,488). If desired, other derivatives of formula VII may be prepared. For example, in order to prepare the derivatives wherein Z is hydroxy, the corresponding oxo group can be selectively reduced with lithium aluminum tri-(lower alkoxy)-hydride or alkali borohydride, e.g., sodium or potassium borohydride, at low temperatures. Derivatives wherein Z is lower alkoxy, for example, tertiarybutoxy, can be obtained from the corresponding hydroxy derivative by reaction under acid conditions with isobutylene by means known in the art. l-Carboxy-lower alkanoyl derivatives of formula VII can be conveniently obtained by reacting dibasic lower alkanoic acids such as, succinic acid and phthalic acid and the like, with corresponding compounds containing the hydroxymethylene moiety. Other derivatives in accordance with the definition of Z can be obtained by methods known to those skilled in the art.

The bicyclic ketone of formula VII can be converted to acid compounds of formula VIII by reaction in accordance with Step (I) of Reaction Scheme A with a base sufficiently strong to afford the corresponding anion of the bicyclic compound via conjugate enolate formation. Exemplary of the suitable bases for this reaction are alkali metal amides such as sodium amide and the like; alkali metal alkoxides such as lithium methoxide and the like and alkali metal hydrides such as sodium hydride. Generally, it is preferred to conduct this reaction at room temperature although temperatures from about -40 C. to the boiling point of the reaction mixture can be utilized. The reaction is conveniently carried out in liquid ammonia or in the presence of an organic solvent inert to the reactants such as dimethyl-sulfoxide, dimethylformamide; hydrocarbons, e.g., benzene and toluene; and ethers, e.g., diethylether and tetrahydrofuran. A preferred solvent for this reaction is dimethylsulfoxide. This intermediate enolate bicyclic reaction product can be isolated by conventional techniques such as, for example, by removal of the solvent using vacuum distillation.

The anion which is thus obtained as a residue can be carboxylated by reaction with excess carbon dioxide to afford the 4-indane carbocyclic acid of the formula VIII. The carboxylation can be suitably effected by employing solid carbon dioxide in the form of Dry Ice or passing gaseous carbon dioxide into the reaction medium. Exemplary of the desirable solvents for this reaction are any of the aforementioned listed solvents which can be employed to prepare the anion with the exception of liquid ammonia, which is basic and dimethylsulfoxide, which tends topromote decarboxylation. In cases wherein liquid ammonia or dimethylsulfoxide is employed to prepare the anion, an inert solvent should be substituted when conducting the carbonation reaction. Suitable reaction temperatures are in the range of C to about 40 C. Most preferably the reaction is initially conducted at the lower end of this range for a period of about 6 hours and then the reaction mixture is allowed to warm to about room temperature during four hours followed by an additional period of standing at room temperature for 12 hours. Separation of the desired reaction product from the reaction medium can be effected by extraction. The extraction is suitably conducted in a hydrocarbon solvent in the presence of a dilute base such as sodium hydroxide or lithium carbonate to form the corresponding water soluble salt of the acid. Base extraction is employed so as to remove the desired product from the starting material. The aqueous layer is separated and carefully acidified to a pH of between 2.5 and 4.5 with dilute mineral acid and the desired product is then obtained by conventional techniques. Although the reaction can be suitably conducted at atmospheric pressure, increased yields can be obtained by conducting the reaction under higher pressures, e .g., in the range of 450 to 550 psi. Carboxylation takes place only at C-4 position on the indane nucleus in agreement with the preference for heteroannular conjugate anion formation with compound VII 7 Inasmuch as the ultimate goal of this invention is to produce a compound of the formula I-b containing a Qba-configuration, it is clear that the hydrogenation of the compound of formula VIII in accordance with Step (2) of Reaction Scheme A must predominantly proceed so as to yield a trans-hydrogenation product with respect to the two rings of the S-indanone or the corresponding 2-napthalenone compounds. A feature of this invention is that the desired hydrogenation to yield a transfused bicyclic structure can be effected in extremely high yields. The hydrogenation is conducted in the presence of a catalyst preferably a noble metal catalyst, such as palladium, rhodium, iridium, platinum and the like. Especially preferred is the palladium catalyst. The noble metal catalyst can be utilized with or without a carrier and if a carrier is used, conventional carriers are suitable. It is preferred to use palladium on barium or calcium sulfate. Especially preferred is 10 percent Pd/BaSo The ratio of catalyst to substrate is not critical and can be varied. However, it has been found advantageous to use a weight ratio of catalyst to substrate from about 1:1 to about 1:10.

Especially preferred is a ratio of 1:3. The hydrogenation is suitably effected in the presence of an inert organic solvent for the particular compound of formula VIII being hydrogenated, for example, a lower alkanol, such as methanol, isopropanol or octanol; ketones for example, lower alkyl ketones such as acetone or methylethyl ketone; lower alkyl esters of lower alkanoic acids such as ethyl acetate; lower alkyl ethers such as diethyl ether to tetrahydrofuran; aromatic hydrocarbons such as toluene or benzene and the like. It is especially preferred to conduct the hydrogenation using a lower alkanol as the solvent and it is preferably conducted under non-acidic conditions. Suitably, the hydrogenation is conducted under neutral conditions. It can be conducted at atmospheric pressure or below or above atmospheric pressure, for example, at pressures of as high as about 50 atmosphere. Also, the hydrogenation can be conducted at room temperature or temperatures above or below room temperature. As a matter of convenience, it is preferred to conduct the hydrogenation at room temperature. The hydrogenation is effected by utilizing conventional techniques, for example, the hydrogenation should be stopped after the uptake of the equivalent of hydrogen or if the absorption of hydrogen ceases before the uptake of an equivalent of hydrogen, it is advantageous to then add more catalyst and further hydrogenate. It will be appreciated that another significant aspect of this hydrogenation step lies in that the hydrogenation of the compound of formula VIII to afford the compound of formula lV-f proceeds without substantial decarboxylation of the substituted indane of formula VIII. Depending on the hydrogenation conditions used, the group represented by Z in formula VIII can be modified during the hydrogenation. For example,

under the above-described hydrogenation conditions, when Z is OR and R is a group such as alkoxy-lower alkyl or tetrahydropyranyl, such group can be split off during the hydrogenation procedure. A preferred group for R in which to conduct the hydrogenation and many of the subsequent other reactions is alkyl, especially, t-butyl.

The thus obtained saturated compound of formula IV-f can be converted to the 4-methylene-trans-fused compounds of formula IV-a by employing a modified Mannich-type reaction in accordance with Step (4) of Reaction Scheme A. The conversion can be effected using formaldehyde in the presence of primary or secondary amine salts. Suitable salts which may be employed are those derived from strong mineral or organic acids such as for example, hydrogen halides, preferably as the chloride, sulfuric acid, oxalic acid and the like, such as for example, piperidine hydrochloride. The reaction can be suitably carried out at a temperature range of from to about 80 C. A preferred tem perature range for this reaction is l5-40 C. While the ratio of reactants used for the reaction is not critical, it has been found advantageous to use approximately a :1 molar ratio of formaldehyde to keto acid and a 0.1:1 to l 1 molar ratio of amine to keto acid.

The reaction is best effected in a dimethylsulfoxide solvent which functions both as a solvent for the reaction and also as a decarboxylating agent. Most advantageous results are obtained when the compound of formula IV- is allowed to react with the Mannich System formed by the addiction of formaldehyde and a primary or secondary amine salt in dimethylsulfoxide solvent, the anion of IV-f is formed first in the dimethylsulfoxide, and it is quenched in situ with the Mannich System. Aqueous formalin (37 4 40 percent) is a generally satisfactory source of formaldehyde for this reaction. Exemplary of the amines suitable for this reaction include secondary amines such as diethylamine, morpholine piperidine and pyrrolidine; primary amines such as methylamine, butylamine and benzylamine. An especially preferred amine for this reaction is piperidine. Other polar solvents such as, for example, dimethylforrnamide and hexamethylphosphoramide which are inert to the reactants may be employed in conjunction with the dimethylsulfoxide. The dimethylsulfoxide solvent promotes decarboxylation, which causes enolization at the bicyclic C-4 position; quenching with the Mannich system in dimethylsulfoxide does not allow the enol to equilibrate toward the preferred C-6 position of trans fused bicyclic systems.

In another aspect of this invention in accordance with Reaction Scheme A, compounds of Formula IV-c may be prepared by alternate process routes (3 9), (5 7 '9),(5 l0) and(5 6 *8).

Thus, the compounds of formula IV-e can be prepared in accordance with Step (5) from the fl-keto acids of formula IV-f in excellent yields employing an organic or inorganic acyl halide preferably thionyl halide, e.g., thionyl chloride; phosphorous trihalide, preferably phosphorous trichloride and phosphorous pentahalide, preferably phosphorous pentachloride.

Thionyl chloride is particularly convenient since the I by-products formed are gases and can be easily separated from the acid chloride. Any excess of the low boiling thionyl chloride canbe easily removed by distillation. This substitution reaction was successfully effected notwithstanding the known prior art [cf., C.B. Hurd et al., J. Am. Chem. Soc. 62, 1548, (1940)] which teaches the inability to prepare B-keto acyl halides by conventional reaction techniques from the corresponding ,B-keto acids. The reaction is suitably conducted at a temperature of from 0 C to the boiling point of the solvent. Suitable solvents for the conversion are thionyl chloride (neat) or in an inert organic solvent such as, for example, benzene, toluene, hexane, cyclohexane and the like.

4-Carbonyl halide indanone compounds of formula IV- e, can be converted to the corresponding esters of formula IV-d by means known in the art. Preferred esters are those wherein R is lower alkyl, especially methyl and ethyl. The esters can be conveniently obtained by reacting the halide with an alkali alkoxide, e.g., sodium methoxide in a solvent such as, for example, lower alcohol, e.g., methanol and the like. Alternatively, the esters of formula IV-d may be obtained by reacting the carboxylic acid with carbonyl diimidazole in tetrahydrofuran solvent, then further reacting the thus obtained produce with the desired aliphatic or aryl alcohol, e.g., phenol, methanol, ethanol and the like at room temperature to the reflux temperature of the solvent in, for example, tetrahydrofuran to obtain the desired ester.

As a further alternate wherein it is desired to prepare 4-alkoxy carbonyl indanones of formula lV-d, the conversion can be effected by treatment of the acids of formula IV-f with an ethereal solution of a diazoalkane such as diazomethane by known means.

The esters of formula IV-d can also be prepared by first esterifying the unsaturated acid compounds of formula VIII to compounds of formula VIII-a in accordance with Reaction Scheme A by the aforementioned methods and then catalytically hydrogenating this unsaturated ester. The steric course of this hydrogenation proceeds so as to yield the C/D-transhydrogenated product. Thus, an identical product of the structure of formula IV-d with C/D-trans-ring fusion is obtained in a similar manner to the case wherein the acid of formula VIII is employed directly as the starting reactant for the hydrogenation step. The bicyclic C/D-trans-structure obtained by the catalytic hydrogenation of the ester may be explained (although applicant is not bound by this theory) by postulating a chelated dienol ester intermediate formed from the non-enolic unsaturated B-keto ester on the surface of the catalyst. However, it should be noted that the rate of catalytic hydrogenation of the B-keto acid of formula VIII was approximately four times as rapid as was the case when the corresponding B-keto ester was employed as the reactant. However, hydrogenation of the ester of formula VIIla employing approximately three times the amount of catalyst employed in the case of the acid of formula VIII under identical reaction conditions resulted in an approximately equal hydrogenation rate.

The fi-keto aldehydes of formula IV-b can be prepared from the acid halides of formula IV-e in accordance with STep (6) of Reaction Scheme A employing a reducing agent such as, lithium aluminum tritertiarybutoxyhydride. The reaction can be carried out in an inert aprotic organic solvent such as, ethers, e.g., tetrahydrofuran and hydrocarbons, e.g., toluene and hexane at a temperature range of -l to 60 C., preferably between the temperature range of 20 and 40 C. When the reaction is carried out within the aforesaid defined temperature ranges, selective reduction of the acid halide can be effected without attacking the free keto group on the -position of the indane of formula IV-e. An alternative method of transforming the acid halide to the corresponding aldehydes can be accomplished by the catalytic hydrogenation of the acid chloride by the Rosenmund Reaction. The technique introduced by Rosenmund consists in adding a small amount of a poisoning agent containing sulfur to the hydrogenation catalyst system.

The indanones of formula IV-c wherein R, Z and m are as defined as aforesaid can be conveniently prepared in accordance with Steps (8), (9) and 10) of Reaction Scheme A depending upon the nature of X, from the esters of formula IV-d, the acid halides of formula IV-e or the aldehydes of formula IV-b.

Suitable requirements for the leaving group as defined by X in the compounds of formula IV-c are that it should function efficaciously in this process aspect, that is, that it be a suitable leaving group for the process of the present invention. Suitable groups which may be employed to form leaving groups are lower alkyl-aryl sulfonyloxy groups such as, for example,

tosyloxy; arylsulfonyloxy groups such as, for example, benzene sulfonyloxy; lower alkyl sulfonyloxy groups such as, for example, mesyloxy (methane sulfonyl); lower alkyl sulfinyloxy; halogen; an acyloxy radical derived from an organic carboxylic acid having one to seven carbon atoms such as lower alkanoic acid, e.g., acetic acid and butyric acid; aryl carboxylic acids such as p-phenyl-benzoic acid and benzoic acid and cycloalkyl carboxylic acids such as cyclopentyl carboxylic acids. Other suitable leaving groups may be selected from the group consisting of wherein each of R and R is independently selected from the group consisting of lower alkyl, aryl and hydrogen, and R and R when taken together to the nitrogen atom to which they are joined, form a 5- or 6- membered heterocyclic ring structure. Thus, the

amino grouping represents secondary and tertiaryamino radicals. It includes monoalkylamino radicals, such as, for example, methyleneamino and butylamino; dialkylamino radicals such as, for example, dimethylamino and dipropylamino, heterocyclic amino radicals, such as, for example, pyrolidino, piperdino, morpholino and 4-methyl-piperizino. The amino radical may also be employed as a leaving group in a modified form by alkylation by known means with a suitable organic ester such as, for example, lower alkyl halide, e.g., methyl chloride or a hydrohalic acid such as, for example, hydrogen chloride to form the corresponding quaternary ammonium salt of the formula reaction sequence which comprises first protecting the 5-oxo moiety on the indanone, reducing the ester group e ster compounds of formula lV-d to the corresponding 4-hydroxy methylene compounds. A preferred protecting group is the dimethoxy derivative which can suitably be obtained by etherification with trimethyl orthoformate. The thus protected 4a-ester can be .reduced employing for example, a suitable reducing agent such as, diisobutyl aluminum hydride, and hydrolyzed to yield the 4-hydroxy methylene compound of the formula (1111011 (IV-c-l) wherein R Z and m are as defined aforesaid.

Alternatively, the ester of formula IV-d in the protected form obtained as described above may be reduced to the alcohol of formula lV-c-l using an alkali metal reducing agent such as sodium metal and lower alcohol or lithium aluminum hydride. Compounds of formula IV-c wherein the leaving group X is lower alkyl sulfonyloxy or lower alkyl-arylsulfonyloxy can be prepared by esterification with an organic sulfonylhalide such as, for example, toluenesulfonyl halide, especially, p-toluenesulfonyl chloride to prepare the tosyloxy derivative or lower alkyl sulfonyl halides, especially methane sulfonyl chloride to prepare the mesyloxy derivative. The above reactions can be suitably conducted at a temperature range of -l to C in the presence of an'organic base such as, for example, pyridine by methods known in the art. The corresponding sulfonic acids may also suitably be employed to effect the esterification in lieu of the sulfonyl halide. Leaving groups wherein X is lower alkyl sulfinyloxy may be obtained in an analogous manner to that above by employing the corresponding sulfinyl halides.

Leaving groups wherein X is defined by the groupmg wherein R and R are defined as aforesaid can be conveniently obtained from the acid halides of formula IV-e in accordance with process route (10) of Reaction Scheme A by a reaction sequence which comprises the steps of (a) reacting the compounds of formula IV-e with a primary or secondary aliphatic or aromatic amine of the formula Ram by known means to form the corresponding amide of the formula R42 (UHfim I H i wherein R Z, m and R and R are as defined aforesaid; (b) protecting the 5-oxo group of the com pounds of formula IV-c-2 by forming the S-ketal analog in a manner similar to that previously described; (c) reducing the amide with a suitable reducing agent such as, for example, diborane or lithium aluminum hydride in an ether solvent such as, for example, tetrahydrofuran which upon removal of the protecting group .by means of dilute mineral acid yields a compound of the formula:

(IV:c-3)

wherein at least either R and R is hydrogen, may also be prepared from the aldehydes of formula IV-b in accordance with process route (8) of Reaction Scheme A by selective condensation with a primary amine of the formula -H NR to form by known means the novel imino Shiff Base intermediate of the formula (IV-c-t) wherein R.,, Z, m and R are defined aforesaid.

The ald-imines of formula IV-c-4 can be conveniently reduced with hydrogen and Raney Nickel to the desired secondary amines.

Leaving groups wherein X is defined as halogen may be conveniently obtained from the alcohols of formula IV-c-l by reaction with for example, hydrogen halides, e.g., hydrogen chloride, phosphorous halides or thionyl chloride by means known in the art. Leaving groups wherein X" is acyloxy as defined aforesaid may be suitably obtained from the compounds of formula IVc-l by reaction with the desired organic carboxylic acid in the presence of a mineral acid such as sulfuric acid or hydrochloric acid at reflux temperature by means known in the art.

In another aspect, the process of this invention relates to the preparation of compounds of the formulas I-a, II and III by reaction of a fi-keto ester or other analog of formula V with compounds of formulas IV-c and IV-a in accordance with Reaction Scheme B. It should be appreciated that compounds of the formulas IV-a and IV-c can be used interchangeably in all of the hereinafter process reactions.

Reaction of compounds of formula V-a with compounds IV-a or IV-c yields bicyclic intermediate of the formula LI which is ring closed to tricyclic compounds of the formula LII. If B" is lower alkyl sulfinyl or lower alkyl sulfonyl then treatment of compounds of formula 16 LII so substituted under chemical reduction conditions (aluminum amalgum) followed by hydrogenation and ring closure via process routes (12) or (13) yields the desired steroids of formulas II or III respectively.

In the case where B" is not the sulfinyl or sulfonyl derivatives noted above, then the conversion of compounds of formula LII proceeds via hydrolysis to compound LIII followed by decarboxylation of the obtained acid. Process routes 12) or 13) may then be followed as above to yield compounds of formulas II or III.

Similarly in the case of compounds of formula LIV and LV prepared from the reaction of compounds of formula V-b and compounds of formula IV-a or IV-c and then cyclization, the ultimate process route depends on the definition of B". When B" is other than a sulfinyl or sulfonyl derivative then compounds of formula [N are hydrolyzed to ultimately yield the acids of formula LVI which upon decarboxylation yield compounds of formula l-a. For the case where B is a sulfinyl or sulfonyl derivative then reduction directly results in the production of compounds of formula I-a.

REACTION SCHEME B (III) (See reaction scheme E) (II) (Sen React D an ion 6 D 2) Schemes (LII) (18 not sulfinyl or sulfonyl derivative) lower alkyl substituted with an) isoxezole ring lower alkyl or whereinR" is hydrogen lower alkyl or lower alkyl substituted with an isoxazole ring; B'- is selected from the group consisting of lower alkoxy-carbonyl, lower aryloxy-carbonyl, cyano, lower alkyl sulfinyl and lower alkyl sulfonyl; V is hydrogen or an alkali metal cation and B, R R R R R R m, X and Z are defined as aforesaid.

The process of this invention in this aspect, comprises employing the bicyclic indanone derivatives of formulaslV-a and IV-c prepared as aforesaid and reacting them with certain subgeneric compounds encompassed by generic compounds of the formula V-b in accordance with process route (11) of Reaction Scheme B to prepare the benz[e]indene compounds of formula l-a. Alternatively, for other subgeneric compounds encompassed by generic formula V-a in accordance with intermediate compounds Ll, LI] and Lil] and then process routes (12) and (13) of Reaction Scheme B, the steroids of formulas II and 111 may be prepared. Thus, for certain compounds subgeneric to formula V, viz formula V-b as defined below, the tricyclic benz[e]indenes of formula l-a may be prepared by means of the building in an annulation reaction steroidal ring B. Alternatively, for certain other compounds subgeneric to formula V-a as defined hereinafter, the steroids of formulas II and III may be prepared by building by means of compounds of fonnula V- a, steroidal rings A and B. Thus, the keto compounds of formula V are employed as one of the starting reactants for the preparation of the tricyclic compounds of the formula l-a or the tetracyclic compounds of formulas II and 111. However, it will be appreciated that the length of the carbon chain varies as exem plified by formulas V-a and V-b below, depending on which class of end products are sought to be prepared.

Thus, the B-keto esters and analogs thereof of formula V-a below, are employed wherein it is desired to prepare the tetracyclic steroids of formulas II and Ill.

(a) by reaction with base, preferably, lithium hydroxide in a lower alcohol solvent, e.g., ethyl alcohol at the reflux temperature of the solvent to form the salt of the acid by saponification of the ester. Subsequent reaction of the thus obtained salt with equimolar quantity of an organo metallic compound, preferably, methyl lithium in tetrahydrofuran in the presence of a minute amount of trip'henylmethane yields the compounds of formula XII. In effecting the conversion, R should be in a protected keto form, e.g., ketal, obtained by reacting the keto compound with a suitable alkylenedioxy, e.g., ethylene glycol or arylenedioxy, e.g., catechol, compound in a manner known per se. Alternatively, the compounds of formula XII can be prepared in accordance with Reaction Scheme C, via process routes (b) and (c) by reacting the compounds of formula X with a lower alkyl sulfinyl methylene compound, e.g., methyl sulfinyl carbanion [cf., E.J.Corey and M. Chaykovsky, J. Am. Chem. Soc. 86, 1639 (1964)] to yield REACTION SCHEME C 2C 03%) (XII) wherein R R R and R' are defined as aforesaid and R is lower alkyl or aryl, intermediates of formula XI. The compounds of formula XI can if desired, be

oxidized to the sulfonyl derivatives with an oxidizing wherein R is aryl or lower alkyl in accordance with process route (e). The preferred condensing agent is sodium hydride although alkali lower alkoxides, e.g., sodium alkoxide may also be suitably employed. The reaction is conveniently conducted in an ether solvent such as, for example, diethylether or tetrahydrofuran, the former being preferred at the reflux temperature of the solvent.

Illustrative of the ,B-keto ester and other analog compounds of formula V-a which may be employed as starting reactants wherein it is desired to prepare the steroids of formulas II or III include 6-(2-methyl-l,3- dioxolan-2-yl)-3-oxohexanoic acid ethyl ester; 6-(2- ethyl-l,3-dioxolan-2-yl)-3-oxohexanoic acid ethyl ester; 3,7-dioxo-octanoic acid methyl ester; 6-(2 methyl-l,3-dioxolan-2-yl)-3-oxohexanoic acid propyl ester; 3,7-dioxo-decanoic acid ethyl ester; l-methylsulfinyl-5-( Z-methyl-l ,3-dioxolan-2-yl )-2-pentanone and the like. By referring to the general formula IV, it can be thus appreciated that when it is desired to prepare the compounds of formulas II or III, the selections of the variables of formula V should be as follows: R is where R R R R and B are defined aforesaid.

The fl-keto esters and other analogs of formula Vb below, are employed wherein it is desired to prepare the tricyclic compounds of formula I-a or lower alkyl; B, R and R" are defined as aforesaid.

The compounds of formula V-b, for example, ethyl propionyl acetate, may be prepared in a similar manner to the compounds of formula V-a in accordance with process step (e) by employing in Reaction Scheme C (the Claisen Condensation Stop) butanone in lieu of the compounds of formula XII.

Exemplary of the B-keto ester and other analogs of formula V-b which may be employed as starting reactants wherein it is desired to prepared the tricyclic compounds of formula I-a include ethyl propionyl acetate, methyl propionyl acetate, ethyl aceto acetate, ethyl butyro acetate, butyro acetonitrile, acetoacetonitrile, l-methyl-sulfinyl-Z-butanone and lmethyl-sulfonyl-2-pentanone.

Compounds of formula Vb wherein the alkyl group is substituted with an isoxazole ring may be prepared from suitably substituted oxo-esters by procedures exemplified by Reaction Scheme C--l.

REACTION SCHEME C-l where B, R, R and R, are defined as aforesaid.

The 4-carbonyl-5-oxo-ester XXIV, e.g., ethyl-4- acetyl-S-oxohexanoate, is initially reacted with hydroxylamine or an acid salt thereof, e.g., hydroxylamine hydrochloride in Step (a) of Reaction Scheme C-l to produce the isoxazole substituted ester XXV. This reaction is conveniently conducted under an inert atmosphere, e.g., nitrogen, in lower alkanol solvent, e.g., ethanol with an added organic base present such as a trialkylamine, preferably triethylamine. The reaction temperature is not broadly critical. The reaction may be run at room temperature although higher or lower temperatures could be used, if desired.

The ester compound XXV may then be converted to the lithium salt XXVI in Step (b) by treatment with lithium hydroxide in a lower alkanol such as ethanol at elevated temperatures, preferably the reflux temperature of the reaction medium. In the following reaction, Step (c), lithium salt XXVI is reacted with a methylating agent suchas methyl lithium in an ethereal solvent such astetrahydrofuran at temperatures below room temperature, preferably at about C. to yield the methyl ketone XXVII.

The final reaction in this procedure, Step (d), involves reacting methyl ketone XXVII with a di-lower alkyl carbonate such as ethyl carbonate in the presence of a metal hydride, preferably an alkali metal hydride, most preferably sodium hydride to yield the isoxazole variant of formula Vb-l. This reaction is conducted above room temperature, preferably at mild reflux in an ethereal solvent such as ethyl ether.

Illustrative examples of isoxazolyl moieties which can be prepared according to the aforesaid Reaction Scheme C-l include: 3,5-dimethyl-4-isoxazolyl. 3- methyl-4-isoxazolyl 3,5-diethyl-4-isoxazolyl, 5-ethyl-4- isoxazolyl, 3methyl-Sphenyl-4-isoxazolyl, 3-ethyl-4- isoxazolyl and the like.

While certain groups exemplified by the definition of the term B have been illustrated in the B-keto ester and other analogs of formulas V-a and V-b, it is to be understood that any other equivalent electron withdrawing group or groups of electronegative nature can function as well. All that is required for the B segments of the molecule for the process of the reaction of the compounds of formula IV with the compounds of formula V is that it function efficaciously in this process aspect, that is, that it be a suitable electron withdrawing group so as to activate the hydrogen atom on the methylene group next adjacent to the carbonyl group. Preferred electron withdrawing groups are the alkoxy carbonyl esters, especially ethoxy carbonyl. The fi-keto nitriles, e.g., aceto-acetonitrile of formula IV-b may be prepared by reaction of acetonitrile phenyllithium and diethylamine at a temperature range of l0 to C. and hydrolyzing in dilute acid the thus obtained imine intermediate to the desired product [cf., Ann. 504, 94 (1933)]. The compounds of formula V-a wherein B is defined as lower alkyl sulfinyl methylene can be readily prepared from the esters of formula X in processstep (b) of Reaction Scheme C. Compounds of formula V-a, wherein B is defined as lower alkyl sulfonyl methylene can be prepared by exidation of the lower alkyl sulfinyl methylene derivatives of XI byknown means. The compounds of formula V- b, whose preparation is not heretofore described or otherwise known, may be prepared in an analogous fashion to compounds of formula V-a.

In a further aspect, the synthesis of the present invention relates to the preparation of steroids of the formulas II and III in accordance with Reaction Scheme B by means of reacting a'carbonchain of the formula V-a with a bicyclic compound of the formulas IV-a or lV-c. In Reaction Scheme D, the numbers are assigned to Roman numerals for identification. schematically, the sequence of reactions involved in the synthesis of 19- norsteroids is illustrated. In a preferred embodiment l9-nortestosterone is prepared as shown by substituent groups in parens. As used in Scheme D and in future Schemes, the notation of a substituent group in parenthesis above or besides a general substituent letter designation is meant to indicate a specific embodiment which is described in the text relating to the Scheme in question.

In the Michael addition, process step (a) of Reaction Scheme D, the precursors to the steroidal A and B rings are built up in a single annulation reaction. The reaction is conducted in the presence of a base sufficiently strong to form the anion of the B-keto ester. Exemplary bases are for example, alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tertiary butoxide and the like; alkali metal hydroxides such as sodium hydroxide and the like; alkali metal hydrides such as sodium hydride, lithium hydride and the like; alkali metal amides such as'lithium amide, sodium amide and the like; methyl sulfinyl carbonion (i'.e., the anion from dimethyl sulfoxide). Especially preferred are the alkali metal lower alkoxides. The reaction can be conducted at a temperature range of from about -5 to about l00 C. However, it is especially advantageous to conduct a reaction within a temperature range of from 0 to 25 C. Moreover, the reaction is suitably conducted in the absence of oxygen, for example, in an atmosphere of inert gas such as nitrogen or argon. It is convenient to conduct the reaction in the presence of an organic solvent inert to the CT QN HE EQ- (CH3)OR2 (t-butyl) L0 1 0 2Rs(C2H5) z (Va3) (NAM) oHnom (t-butyl) H (b) 0 v'v 2 o(C2Ha) (XVI) (C H!) 0 R2 (tbutyl) (XVII) c0211 onnom (t butyt) (CHQOH R4 R4 H H I H m i i 111 H H O xvm) L0 IB-NOrsteriOdS 0 (II-a) I (IQ-Nortestosterone) reactants as well as the-intermediates of formula XVI. Such solvents are for example, dimethylformamide, dimethylsulfoxide and aromatic hydrocarbons, such as, for example, benzene, toluene and xylene. Other suitable solvents include the ethers such as diethylether, tetrahydrofuran and the like and lower alkanols such as methanol, ethanol and the like. The concentration of reactants is not critical but it is preferred to use a 1:1 molar ratio of reactants of formulas IV-a-l and V-a-3. One may add the reactant of formula V-a--3 to a reaction mixture already containing the base and the bicyclic indanone of formula IV-a-l. However, the reaction can also be efiected by placing all the reactants substantially together or preferentially the reactants of formula IV-a-l can be added to a mixture containing the base and the reactant of formula V-a-3 (reverse addition). When employing as a starting reactant, the compounds of formula IV-c in lieu of the reactants of formula IV-al, the same process conditions are employed and products obtained although the reaction does not necessarily have to proceed by way of a Michael addition mechanism. The sidechain of the reaction intermediate XVI assumes the thermodynamically favorable equatorial configuration under the equilibrating reaction conditions. The alpha orientation of the sidechain is extremely important for the construction of ring B with the proper stereochemistry. No ring closure occurred at this stage because of the preferred enolization of the keto group towards the ester function. Following the Michael addition of the ,6- keto ester of formula V-a-3 to the bicyclic CID-transindanone of formula IV-a-l, the thus obtained compounds of formula XVI is saponified to remove the ester group and cyclized in accordance with process step (b) of Reaction Scheme D. The cyclization should be effected under reaction conditions which do not cleave the cyclic ketal protecting group. Exemplary 'basic cyclization reagents are for example, a dilute aqueous solution of alkali metal hydroxides or alkaline earth metal hydroxide, such as for example, sodium hydroxide, lithium hydroxide, calcium hydroxide and the like. The cyclization is suitably conducted in an inert organic solvent such as for example, hydrocarbons, e.g., benzene, toluene and ethers, e.g., tetrahydrofuran. The cyclization can be conducted at room temperature or above room temperature but as a matter of convenience, it is preferable to conduct the reaction at about room temperature. The ester group of 50 the bicyclic intermediate of formula XVI can be removed by saponification of the ester in accordance with Step (b) of Reaction Scheme D to afford the corresponding acid of the formula XVII (after acidification) and decarboxylation to compounds of the formula XVII-l for example, in refluxing toluene under an inert atmosphere such as for example, nitrogen in accordance with Step (c) of Reaction Scheme D. For other cases wherein the electron withdrawing group of formula V (B) is other than ester, e.g., for example, lower alkyl sulfinyl methylene or lower alkyl sulfonyl methylene, the removal of the grouping can be effected by reduction with a reducing agent such as, for example, aluminum amalgam. For cases wherein the electron withdrawing group is nitrile, the reaction can be suitably conducted in an analogous manner to that wherein the electron withdrawing group is an ester as discussed above.

The hydrogenation of the A -double bond of the compounds of formula XVII-l to the compounds of formula XVIII can beeffected in accordance with Step (d) of Reaction Scheme D in a lower alcohol solvent such as, for example, ethyl alcohol in the presence of a base, preferably, triethylamine. l9-Nortestosterone can be obtained from the compounds of formula XVIII by hydrolysis and cyclization by refluxing in a mineral acid such as, hydrochloric acid or sulfuric acid in a lower alkanol solvent such as methanol in accordance with Step (e) of Reaction Scheme D.

It should be noted that the process steps exemplified in Reaction Scheme D can be utilized to prepare norgestrel. This can be efl'ected by preparing the 7afl-ethyl analogs of formula IV-a-I as described on page 9 of the instant specification employing the reaction steps (a), (b), (c), (d) and (e) of Reaction Scheme D followed by oxidation utilizing for example, Jones Reagent and ethinylation in accordance with procedures described hereinafter. It will be further appreciated that by employing the optically active 7aB-ethylenantiomer of formula IV-a-l of Reaction Scheme D, one can prepare optically active norgestrel.

It will be appreciated that this aspect of the process of the invention for the synthesis of steroids of the formula IIof which IQ-nortestosterone is a specific exemplar as set forth in Reaction Scheme D, can be modified so as to yield other pharmaceutically valuable steroids of formula II, well known in the art, wherein R is other than hydrogen, e.g., lower alkyl by selectively alkylating the A -compounds of formula XVII-l with a lower alkyl halide in the presence of a strong base, preferably lithium in liquid ammonia at temperatures in the order of 40 C. in an inert solvent such as, for example, diethyl ether by means known in the art.

It is possible to produce l9-nortestosterone from compounds of formula XVII by an alternate procedure which is illustrated by Reaction Scheme D-l.

REMACT QLT D1 (CH 0 RAt-butyl) (CH3) 0 R2 (t-butyl) R4 K Br I (a H H v v-o L H) V go 0 0/ 0 0% C 0 1H (5 02-lower alkyl (XVII) (XXXIII) l (0 H 0 Rz(t-butyl) CH) O RQW-butyI) R4 i R4 H H H u l l I (c) I H i H H ,0 H O W I O oyv C 0 zlower alkyl 1 0 :-lower alkyl (XXXV) (XXXIV) (CH3) R1 (t-butyl) (CHa)0H (II-a) l -norsterolds (l9-nortestesterone) (XXXVI'B) where W, R and R, are defined as hereinbefore, and V is hydrogen or an alkali metal cation, e.g., sodium or potassium.

In Step (a) of Reaction Scheme D-l the tricyclic acid XVII is esterified in a manner well known in the art. For example the methyl ester, which is a preferred embodiment, is obtained by utilizing diazomethane in an inert organic solvent, e. g., ether.

The resulting tricyclic ester of the formula XXXIII is then catalytically hydrogenated in Step (b) of Reaction Scheme Dl at normal conditions using a noble metal catalyst, e.g., 5 percent palladium on charcoal, and a lower alkanol solvent such as, for example, ethyl alcohol in the presence of a base, preferably triethylamine to produce the ketal protected saturated tri-cyclic ester XXXIV.

Careful hydrolysis (Step c) of the ketal ester XXXIV using aqueous dilute acid, e.g., 0.0lN HCl at about C. results in selective deketalization to yield the diketone ester XXXV. Cyclization of the latter compound may be accomplished in Step (d) using dilute base, e.g., OLlN NaOH in a water miscible ethereal solvent such as tetrahydrofuran or dioxane at about 20 C. to yield the steroid acid salt XXXVI (V alkali metal cation) which can be converted to the free acid on acidification.

The compounds of formula XXXVI may be directly converted into l9-nortestosterone by refluxing with 1N mineral acid, e.g., l-ICI which effects decarboxylation, and hydrolysis of the protective group in Step (e) of Reaction Scheme Dl. This procedure may also be accomplished in stepwise fashion. Thus, treatment of compound XXXVI with methanol saturated with HCl gas at 0 at atmospheric pressure in Step (f) will free the l7-hydroxy group while preserving the 6-carboxyl function, e.g., compound XXXVI-a. Subsequent treatment of the latter compound with 1N aqueous hydrochloric acid at reflux will yield the desired 19- norsteroid, e.g., l9-nortestosterone when R, methyl by decarboxylation in Step (g). In another preferred embodiment of this process R is ethyl whereby an intermediate useful in the preparation of norgestrel is obtained.

It is further within the scope of the present invention to utilize the alkali metal salt, e.g., the sodium salt of the tri-cyclic acid XVII in an alternative scheme summarized below in Reaction Scheme D2.

26 REACTION SCHEME D2 cm 0 R, (t-butyl) I (CH3) 0 R2 (t-butyl) 1 H I I i r E r a H w 0 (a) w 0 o 0 (XVII-a) (xxxvn C H3) 0 R 2 (t-butyl) (XXXVIII) be) 3) 0 2(t-buty1) 5 1 HY O (XXXIX) \(e) 9 (canon R4 R4 H H (F H i s it a H H O (l) 0 (II-a) 19-Norsterolds (IQ-Nortestosterone) H where W, R and R, are defined hereinbefore and M is an alkali metal cation preferably sodium or potassium, most preferably sodium.

Thus, the alkali metal salt of the tricyclic carboxylic acid XVII, e.g., XVII-a in Step (a) in Reaction Scheme D2, is hydrogenated in water using a noble metal catalyst, e.g., 10 percent palladium on charcoal to give the tricyclic keto carboxylic acid salt XXXVII which can be converted to the acid, if desired, by acidification in a manner known per se. Removal of the ketal group may then be accomplished in Step (b) by using dilute aqueous mineral acid, e.g., 0. IN I ICl at about 20C. to

ii. Steps (d) and (f),i.e., first simultaneous cycliza tion and removal of the protective group by the action of concentrated mineral acid, e.g., hydrochloric acid at 20 C. to give hydroxy acid XL followed by decarboxylation as above; and

iii. Step (g), i.e. by simultaneous cyclization, removal of the protective group and decarboxylation by acidifying the hydrogenation filtrate using aqueous mineral acid until the solution is 1N in acid, e.g., hydrochloric acid in the presence of a lower alkanol, e.g., methanol, at elevated temperatures, preferably at the reflux temperature of the reaction medium.

In general it is desirable to conduct the cyclization, hydrolysis and decarboxylation reactions under an inert atmosphere such as, for example, under a nitrogen atmosphere.

Moreover, when R of the B-keto ester or other analogs thereof of the formula V-a is 0x0 and not in a protected ketal form, A -steroids of formula III in lieu of the steroids of formula II will be produced in accordance with Reaction Scheme E. Thus, in a specific embodiment exemplified in Reaction Scheme E, steroids encompassed by the genus of the formula III are prepared. The dione ester of the formula V-a-4 is reacted with the methylene Ketone of formula lV-a-l in accordance with Step (a) in the presence of an alkali alkoxide such as 0.1N sodium methoxide in a methanol solvent using a temperature range of 020 C. to yield the substituted trione of formula XVI-a. The compound of formula XVI-a in accordance with Step.(b) of Reaction Scheme E can be hydrolyzed and ring closed using a hydrogen halide acid such as hydrogen bromide in aqueous acetone at a temperature of approximately 20C. to yield the acid compound XVII-a. Decarboxylation of compound XVII-a in refluxing toluene in accordance with Step (c) yields compound XVlI-l-a. The diene steroids of the formula III-a can be obtained in accordance with Step (d) of Reaction Scheme E by cyclizing the compound of formula XVII-l-a using an alkali alkoxide preferably potassium t-butoxide in benzene. The l7-hydroxy diene steroids of formula III-b are obtained in accordance with Step (e) of Reaction Scheme E by refluxing in methanol-H O in the presence of acid, preferably hydrogen chloride. I

REACTION SCHEME E (CH3) 0 R2 (lJ-butyl) (CH3) O R: (t-butyl) mill : 0 l H 1 0 CH2 C zR5( 2 i) Q K Q a) (IV-a-l) (V-a-4) (XVI-a) 0390112 (t-butyl) (CH3) 0R2 (t'butyl) 0119012, (t-butyl) H H E E i H (o H (d) (e) 0 H 0 o (XVII-a) (XVII-l-a) (III-a) ,(CH;)OH 0R1 (t-butyl) XVII-1 Reaction Scheme Alternatively, treatment of compound XVII-a with base in Step (g) using the same reagents and conditions as described for Step (d) above yields the tetracyclic carboxylic acid XLI which on treatment with concentrated mineral acid, e. g., hydro-chloric acid, at elevated temperature, e.g., 70*100 C. preferably about 80 C. yields the steroid compound of formula III-b in step (b).

The keto compound XVII-l of Reaction Scheme D can also be convertedto steroidal intermediates of the formula XVII-l-a via mild hydrolysis of the ketal moiety employing 0.l N hydrochloric acid in a solvent such as tetrahydrofuran at a temperature of approximately C. in accordance with Step (f) of Reaction Scheme E. Steroids of formula III can be converted to pharrnaceutically valuable estrogens byknown means (cf. Velluz et al., Angewandte Chemie 72, 725 1960).

Compounds of formula I-a-E2 wherein R, is methyl substituted with an isoxazolyl moiety may be prepared in a manner directly analogous to the procedure described in Reaction Scheme D. This is summarized below in Reaction Scheme El where process steps (a), (b) and (c) are identical as to reagents and reaction conditions as previously described for steps (a), (b) and (c) of Reaction Scheme D.

REACTION SCHEME E-l In a further aspect, the present invention relates to the preparation of A-"'-steroids of the formula III by reacting a vinylogous beta keto ester or other analogs of the formula wherein B is defined as aforesaid with compounds of the formula IV-a and IV-c.

REACTION SCHEME F (CHQO (t-butyl) (XXIII) (III-b) A preferred value of B is lower alkoxy carbonyl. Especially preferred is methoxy carbonyl and ethoxy carbonyl. Thus, in a specific embodiment exemplified in Reaction Scheme F, diene steroids of the formula III-b are prepared. The vinylogous beta keto ester of formula VI-a is reacted with the methylene ketone of formula lV-a l in accordance with Step (at) of Reaction Scheme F in the presence of an alkali lower alkoxide, preferably 0.1 N sodium methoxide in a lower alcohol solvent, preferably, methanol or ethanol, at a temperature range of 0 to 20 C yielding the dione of formula XXIII. The diene steroid of formula III-b can be conveniently obtained from the compound of formula XXIII by cyclization using refluxing mineral acid, preferably, l-N-hydrochloric acid in a lower alcohol solvent, preferably methanol.

In still another aspect of this invention, compounds of the formula IV-f, in Reaction Scheme A, can be converted to compounds of the formula XXIV below, which are subgeneric to the compounds of formula IV (XXIV) XXIV can be converted to their A unsaturated analogs by a bromination-dehydrobromination procedure. The A -CID trans indanones can be converted by methods described in the above cited reference to the tricyclic compounds of the formula I which in turn can be converted to pharmaceutically valuable steroids by procedures hereinafter described.

In a further aspect, the synthesis of the present invention relates in accordance with Step (11) of Reaction Scheme B to the preparation of 2,3,3a,4,5,7,8,9,9a,9bdecahy dro-3a-alkyl-7-oxol H-benz[e ]indenes and 4,4a/3,4bba,5 ,6,7,8,8a,9, 1 -decahydro-8aB-alkylphenanthrene-2(3H)-ones which contain in the 2-position and 8'position, respectively, an oxo substituent or an 8,8()llt moiety wherein R has the meaning given in the text accompanying formula IV. Many members of this class of known compounds which are valuable intermediates in the synthesis of steroids, for example, benz[e]indene derivatives contain asymmetric centers at positions-9a,9b,3a and also at the 3-position if the substituent thereat is other than oxo. Thus, of the 3-oxo compounds, there are eight possible different stereoisomers, whereas of the compounds containing a 8-OR substituent, there are possible sixteen stereoisomers.

In a preferred embodiment of this aspect, the synthesis relates to the preparation of the 9aB,9ba,3aB- stereoisomers of the benz[e]indene series, its optical antipode and racemate thereof and in the case where the 3-substituent is other than oxo, the 9a,l3,9ba, 3aB,3 B-stereoisomer, its optical antipode and the racemate thereof. The corresponding hydrophenanthrene-Z- ones, i.e., 4aB,4ba,8a,8-stereoisomers may also be prepared. The especially desired end-products of the synthesis of this invention are the enantiomers with the absolute configuration shown in the following formula:

wherein R R.,, Z and m are as defined aforesaid.

The compounds of formula I--a can be obtained by commencing the synthesis of this invention with an optically pure starting material of formula IV or by commencing the synthesis of this invention with a racemic (i.e., dl) starting material of the formula IV and effecting resolution at any intermediate stage or after the desired end-product of formula I has been obtained as the racemate.

Referring to Reaction Scheme G, wherein the compounds are assigned Roman numerals for identification schematically, the sequence of reactions involved in the synthesis of a specific embodiment, namely, the benz[e]indenes of formula i-a' are illustrated. Thus, ethylpropionylacetate is reacted with a compound of formula IV-c-l wherein the nucleophilic leaving group X exemplified is mesyloxy (compounds of formula lV-a-l can also suitably be employed) to yield compounds of formula XV in accordance with Step (a). Reaction conditions employed for this conversion are identical with that exemplified hereinabove in process step (a) of Reaction Scheme D for the preparation of compound XVI. Compound of formula l-a' is obtained in accordance with process step (b) via cyclization which includes an internal aldol condensation and dehydration using a strong mineral acid, e.g., 2N- hydrochloric acid in a lower alcohol solvent, e.g., methanol, at the reflux temperature of the solvent. The conversion of compounds of the formula XV of Reaction Scheme G to compounds of the formula I-a' can also be conducted under reaction conditions employed in Steps (b), (c) and (e) of Reaction Scheme D as seen in Steps (c), (d) and (e) of Reaction Scheme G respectively, Intermediates XXXIII and XXXlVare involved in this sequence.

As indicated above, the 2,3,3a,4,5,7,8,9,9a/3,9badecahydro3aB-alkyl-7-oxo-lH-benz]e[indenes and the 4,4a,8,4bba,5 ,6,7,8,8a,9, I 0-decahydro-8aB-alkyl-3H- phenanthren-Z-ones of formula I obtained by the process of this invention are useful as intermediates REACTION SCHEME G Preparation of the tricyclic compounds of Formula I (C H3) 0 Rn(t-butyl) (Euro SO7CH3 1V 1 (CH3) or 1 (CHQORzU-butYl) 55 Y1 t't CH2 (IV-a-l) (a) (CHa)ORi(t-butyl) (CH3)OR1 R4 R4 cm) 11 (CH3) HY l l l l as: l H at: H

2 5(C2Ht) COZH (XV) (XXXIII) (W1 l (d) a) 0H (CH3) 0 Rz(t-butyl) R4 R4 \i/ (e) (CH3) H (CH3) H 1 l fii yi H fit??? H (1-13) V (XXXIV) where R R R and R are as hereinbefore defined.

In the formation of the tetracyclic steroid nucleus in accordance with Reaction Scheme H. The benz[e]in- I ing to methods known per se. The patent literature contains many references which are illustrative of methods to effect conversion of the tricyclics of formula I to known steroids of which US. Pat. Nos. 3,115,507; 3,120,544; 3,128,59l; 3,150,152 and 3,168,530 are exemplary.

The ultimate utility of the tricyclic intermediates de- 'pends on the nature of R, and R.,. For example, compounds wherein R is hydrogen may lead to either 19- nor steroids (Velluz et al., Angewandte Chemie 72, 725, (1960); or alternatively to la-l9-nor-steroids (French Pat. 1,360,55) depending upon the reaction conditions. Further, the tricyclics wherein R, is hydrogen may be converted into 19-nor-retro(9B,l 0asteroids (Velluz et al., Tetrahedron Suppl. 8, Part II, 495 (1966) and estrogens, viz compounds having an aromatic A ring e.g., estradiol (Velluz et al., Angewandte Chemie 72, 725 (1960). On the other hand, compounds wherein R, is alkyl may lead to compounds of the 9a,l0a-serie s (Velluz et al., Angewandte Chemie 77, 185, (1960) or alternatively to compounds of the retrosteroid series viz those having inverted centers of asymmetry at positions C and C,,,, i.e., the 9fl,l0a-steroids (Belgium Pat. 663,193). Compounds wherein R, is lower alkyl may be obtained wherein R of the compounds of formula V-b is lower alkyl (other than methyl).

As illustrated by the following Reaction Scheme H,

I in the first step of this reaction, the compound I may be hydrogenated to the tricyclic compound XIX. The 4 reaction is preferably effected with a noble metal catalyst, e.g., a palladium-charcoal or a lower-rhodium Tricyclic compounds of formula I for values wherein R, is hydrogen may be converted by means known in the art to compounds of formula XXI wherein R, is hydrogen viz steroids of the l9-nor-lOa-series. Further, the tricyclic compounds of formula I wherein R, is hydrogen may be alternatively converted to compounds of formula II viz the normal steroids of the 9a,l0fl-(normaI-l9-nor series). This is described more fully in Angewandte Chemie 77,185 (1965), Velluz, Valls and Nomin and Angewandte Chemie 72, 725 (1960), Velluz et al.

A preferred procedure for converting tricyclic compounds of formula I wherein R, is hydrogen to normal steroids of the 9a-l9-nor series of formula II can be effected by reacting the tricyclic compounds with 4-halo- 2- alkoxy butane wherein the REACTION SCHEME H (XXI) 10a-Serles"-sterolds where R R4, C and n are as hereinbefore defined. Halogen is preferably selected from the group consisting of chlorine, bromine or iodine. For example, a tricyclic compound of formula I such as 2,3,3a,4,5,7,8,9B, 9bB-decahydro-BaBB-ethyl-B-oxo- 7-oxo-lI-I-benz[e]indene may be reacted with for example, 4-chloro-Z-tertiarybutoxy-butane in a suitable solvent such as, for example, dimethylformamide or dimethylsulfoxide under a nitrogen atmosphere in the presence of a base such as, for example, sodium hydride or potassium tertiarybutoxide at a temperature range of between 15 and 100 to yield the intermediate I0-[ 3-tertiarybutoxy-butyll-l 3-ethyll 9-nor-desA-androst-9-ene-5,l7-dione. This latter compound can be converted to norgestrel by procedures described more fully in US. Pat. application of Gabriel Saucy, Ser. No.

679,989, filed on Nov. 2, 1967 now US Pat. No. 3,544,598.

4-I-Ialo-2-tertiarybutoxy butane may be prepared from 4-halo-2-butanol by reaction of the latter compound with isobutylene in the presence of a mineral acid such as sulfuric acid or hydrochloric acid at room temperature.

The tricyclic compounds of formula I for values wherein R is alkyl may be converted by methods known in the art to compounds of formula XXII viz steroids of the retro series via catalytic hydrogenation to compounds of the formula XIX and base catalyzed reaction of XIX with for example, methyl vinyl ketone.

Compounds of formula I can also be directly reacted with, for example, methyl vinyl ketone yielding a 5- hydroxy-tetracyclic compound of formula XX. These latter compounds can then be subjected to dehydration followed by hydrogenation or to hydrogenation followed by dehydration to yield a 100: or 9/3, IOa-or l0asteroids of formulas XXI and XXII. These procedures are described in greater detail in Netherlands Octrooiaanvrage No. 6,412,939.

Compounds of formula I-a-E-l where R is lower alkyl substituted with an isoxazole group, preferably (3,5-dimethyl-isoxazole-4-xl)methyl, are obtained by first reacting compounds of formula IV-a or IV-c with compounds of formula Vb-l in the manner previously described for the reaction between generic compounds of formula IV-a or IV-c and formula V-b. The reaction product is saponified and ring closed in base using procedures previously described herein. Acidification followed by decarboxylation gives compounds of for mula I-a-E-l.

Conversion of the isoxazole substituted alkyl variant of formula I compounds into 19-nor-steroids subgeneric to formula II may be accomplished by reference to Reaction Scheme I-I-l.

REAcTIon sqHE rr-1 (XXXII) l I I! H k (b) R where R, R", m, R and Z are as above; 2' is carbonyl or a free or protected hydroxyl and Z" is as hereinafter defined.

The cycloolefin compounds of formula l-a-E-l are hydrogenated to the tricyclic compounds of formula XXVIII in accordance with Step (a) of Reaction Scheme I-I-l. The hydrogenation is preferably effected in a lower alcohol solvent, e.g., ethanol using a palladium metal catalyst and carbon carrier although other noble metal catalysts may be employed. The hydrogenation is conducted under neutral, acidic or weakly basic conditions substantially at atmospheric pressure and room temperature so as to selectively hydrogenate the A*' bond without substantially hydrogenating the isoxazoly moiety. Suitable weak bases for this purpose are mono, di or tri-lower alkyl amines, preferably triethyl amine. It has been found that the use of base in this hydrogenation step aides in selectively promoting the formation of the compound of formula XXVIII which has a trans-anti-trans configuration when trans-anti enones of formula I-a-E-l are employed as reactants.

The conversion of the tricyclic compounds of form ula XXVIII to the steroids of formula II-H-l can be accomplished by alternative reaction methods. Thus, process routes (b), (e), (f) and (g) hereinafter referred to as the heterocyclic anhydrous basic route and (b), (c), (d) and (g) hereinafter referred to as heterocyclic aqueous basic route exemplified in Reaction Scheme H-l can be employed.

The tricyclic compounds of formula XXVIII can be converted to the l9-nor-steroids of formula II-H-l via the heterocyclic anhydrous basic route which comprises sequential process Steps (b), (e), (f) and (g) of Reaction Scheme H-l. Thus, the vinylogous amides of formula XXIX can be obtained from the tricyclic compounds of formula XXVIII via Step (b), in the same U (XXVIII) (XXIX) reaction mixture that was employed to hydrogenate the compounds of formula I-c to the compounds of form ula XXVIII [Step (a)], by the addition of strong base to the reaction medium and then further hydrogenating. Alternatively, hydrogenation of the isoxazole group of the isolated compound XXVIIl can be suitably conducted in the presence of a catalyst, preferably a noble metal catalyst, such as rhodium, palladium, platinum and the like or Raney nickel. The catalyst can be utilized with or without a carrier and if a carrier is used, conventional carriers are suitable. Especially preferred is percent Pd/C. The ratio of catalyst to substrate is not critical and can be varied. However, it has been found advantageous to use a weight ratio of catalyst to substrate from about 1:5 to about 1:25. Especially preferred is a ratio of 1:10. The hydrogenation is suitably effected in an organic solvent, preferably a lower alcohol at room temperature and atmospheric pressure in the presence of strong base, although higher temperatures and pressure may be employed. Preferred bases for the second hydrogenation are strong alkali metal hydroxides, e.g., potassium hydroxide, sodium hydroxide and the like. Treatment of the vinylogous amides of formula XXlX with anhydrous base, in accordance with Step (e) of Reaction SchemeH-l, results in dehydration and acyl cleavage of the compounds of formula XXIX to yield the dihydro pyridines of formula XXXll. Preferred anhydrous bases for this conversion are alkali metal lower alkoxides, especially sodium ethoxide. The reaction is conveniently carried out in a lower alcohol solvent, preferably ethanol. Hydrolysis of the substituted dihydropyridines of formula XXXIl with aqueous alcoholic base in accordance with Step (f) of Reaction Scheme l-l-l yields the diketone compounds of formula XXXI. Cyclization of the latter compounds which are not isolable occurs rapidly to give l9-nor steroids of formula Il-H-l in accordance with Step (g) of Reaction Scheme l-I-l.

It should be noted when employing the anhydrous 4 basic route that the acyl group R" is selectively cleaved, enabling use of mixed isoxazoles, e.g., those wherein R' and R" are not identical.

ous basic route and the heterocyclic anhydrous basic route described immediately aforesaid, lies in the difference between process Steps (e) and (c). In the former case, strong anhydrous base is employed in Step (e) yielding heterocyclic compounds of formula XXXII and in the latter case strong aqueous base such as, for example, aqueous metal hydroxides, preferably NaOI-l, is employed in Step (0) yielding triketones of formula "I. It should be noted, however, that the aqueous basic route is not selective and probably also proceeds via Step (e) as well as Step (c). The diketones of formula XXXI which are obtained in accordance with Step (d) by cleaving the triketones of formula XXX, further react by cyclizing (Step g) to yield steroids of formula ll-H-l. The acyl cleavage effected in accordance with Step (d) is not selective, that is to say it is not possible to predict whether the R group or the R" acyl group will be cleaved. It is, therefore, desirable when employing the aqueous basic route that R' and R" be identical or either R' or R" be hydrogen in order to avoid the obtention of mixed steroidal products. If either R or R" is hydrogen, selective cleavage of the formyl group occurs, thus avoiding mixed steroidal products.

It should be emphasized as one further facet of the stem-selectivity of the instant invention, that when tricyclic compounds of formula XXVIII having a transanti-trans-configuration are employed in Reaction Scheme H-l, steroids of formula II-H-l having a transanti-trans-anti-configuration are produced. This is highly desirable since many pharmacologically valuable compounds possess this configuration.

ln compounds represented by the formulas XXX, XXXI and XXXII of Reaction Scheme H-l, Z" is defined in an identical manner to 2. as defined aforesaid, with the proviso that Z" cannot be a lower alkylenedioxy-methylene, phendioxy-methylene or dialkoxymethylene or ester function. However, the endproducts of formula II-H-l substituted in the l7-position (steroidal numbering) by Z are obtained from the precursors of the formulas which are substituted in the l7-position by Z" by means known in the art.

Additional details on reactions involving'the isoxazole group are to be found in US. Pat. application, Ser. No. 778,314 filed Nov. 22, 1968, inventors Gabriel Saucy and John William Scott.

Compounds of formula I-a when converted into compounds of formula [I wherein R is ethyl and R is hydrogen and Z is carbonyl can be selectively alkynylated by a suitable organic metallic acetylide affording norgestrel 13B-ethyl-l7a-ethinyl-l7-hydroxy-gon-4- ene-3-one). The latter compound canalso be prepared by similar extensions of Reaction Schemes D, D-l or D-2. Exemplary of the suitable alkynylating agents to effect conversion to norgestrel are the alkali acetylides such as lithium acetylide, potassium acetylide, sodium acetylide, etc. The reaction is carried out in the presence of liquid ammonia in suitable solvent systems such as benzene or toluene. The alkynylation is effected preferably at the reflux temperature of the reaction medium although temperatures from --60 to 31 30 are suitable. Exemplary of other suitable reagents to effect the acetylenic addition are ethylaminediamine complex in dimethyl-formamide solvent and Grignard analogs such as mono and his acetylene-magnesium halides by means known in the art. I

Further, the l9nor-compounds of formula II, wherein R is propyl are ovulatory inhibitors (cf., Tetrahedron Letters 127 (1961 Velluz, Nomine et al.). Additionally, compounds of formula I wherein R, is methyl and R is hydrogen have been converted tp the series of formula II, specifically, l9-nortestosterone acetate, J. Org. Chem., 26, 3904 (1961), LJ. Chinn and EL. Dryden. 

2. The compound as in claim 1 wherein B is ethoxy-carbonyl-methylene.
 3. The compound as in claim 2 which is 6-(2-methyl-1,3-dioxolane-2-yl)-3-oxo-hexanoic acid ethyl ester.
 4. The compound as in claim 2 which is 6-(2-ethyl-1,3-dioxolane-2-yl)-3-oxo-hexanoic acid ethyl ester.
 5. The compound as in claim 2 which is 3-oxo-7,7phenylene-dioxy octanoate. 